PROJECT SUMMARY Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that is caused by the SARS-CoV-2 virus. The disease has caused illness in more than 1.2 million Americans within the last 4 months. However, there are almost no data on human cellular immune response towards this virus. Monitoring the kinetics and breadth of cellular immune responses associated with clinical resolution of COVID-19 should shed insight on the human immune response towards this pathogen during natural infection. We will evaluate SARS-CoV-2 antigen specific immune responses in subjects with different degree of disease severity that are infected by either the USA-WAS2/2020 like strain or the FR-HF1465/2020 like strain, the 2 major strains that circulated in Washington state. We will test the hypothesis that coordinated CD4+ and CD8+ antigen specific responses are responsible for clearing of the virus. We will also test the hypothesis that subjects that have severe disease and those that succumb to the disease have dysfunctional CD4+T cell responses. We will use transcriptomics analysis to evaluate whole blood, bulk T cells and antigen specific CD4+ and CD8+ T cells. Data will be stratified according to the viral strains and disease severity. There will be 3 major aims: 1. Characterize of antigen specific immune responses in COVID-19 subjects with severe pneumonia, moderate disease and mild disease, infected by either the USA-WAS2/2020 strain or the FR-HF1465/2020 strain. 2. Characterize epitope specific immune response in subjects with COVID-19. The hypothesis that the functional defect of antigen specific CD4+ T cells in subjects with severe disease will be tested. 3. Characterize host RNA-seq signatures of COVID-19 respiratory infection in whole blood PBMC, bulk and viral antigen-specific CD4+ and CD8+ T cells from COVID-19 subjects infected by either the USA-WAS2/2020 strain or the FR-HF1465/2020 like strain. A better understanding of antigen specific immune responses in human should facilitate the identification of effective drug candidates for treatment and developing new vaccine to prevent infection.